HIV and its rhesus macaque (RM) counterpart SIVmac239 share a pattern of infection and a constellation of pathobiologic features that, in the vast majority of susceptible (untreated) people or RM, results in unremitting infection and progressive immune deficiency. In the first 5 years of this project, our work has strongly linked the inability of SIVmac239-infected RM to maintain CD4+ effector-memory T cell (TEM) populations in extra-lymphoid effector sites above a crucial threshold to the development of overt AIDS. However, we found that the primary determinant of this CD4+ TEM population failure was not in the TEM populations themselves, but rather in the homeostasis of the secondary lymphoid tissue-based CD4+ central memory (TCM) populations that serve as the primary source of TEM production. Indeed, our data indicate that it is the gradual, progressive loss of CD4+ TCM populations (with the consequent reduction in CD4+ TEM production) that sets the clock with respect to disease progression. This finding places the mechanisms that maintain CD4+ TCM homeostasis and regulate TCM differentiation into effector site-homing TEM at the center of AIDS pathogenesis. The overall goal of this project renewal is therefore to characterize the cellular and molecular basis of CD4+ TCM population failure in progressive SIVmac239 infection. We will specifically examine: 1) the extent to which CD4+ TCM survival, proliferation and differentiation is dysregulated in progressive infection and the molecular basis of this dysregulation (with focus on the signaling and function of the common gamma chain cytokines IL-7 and IL-15, and the effect of chronic immune activation on homeostatic regulation), 2) the pathogenic role of proliferative senescence (failure of CD4+ TCM to maintain telomere length and proliferative potential), 3) the contribution that nave cell recruitment (and thymic function) makes towards CD4+ TCM homeostasis in infected RM, 4) the extent to which secondary lymphoid tissue microenvironments supportive of CD4+ TCM homeostasis are lost, and 5) the extent to which viral targeting of CD4+ TCM contributes to their instability. Identification of the defect(s) underlying CD4+ TCM population failure, particularly maladaptive host mechanisms, will be a crucial step in the development of novel immuno-therapeutics aimed at disconnecting viral replication from disease -- treatments with the ability to prevent immune deficiency and/or restore immune function in HIV+ individuals with persistent viral replication. PUBLIC HEALTH RELEVANCE: Although the advent of modern anti-retroviral therapies has been nothing short of miraculous, the danger posed by HIV to infected individuals has not been eliminated, and better understanding of the precise mechanisms that enable HIV to damage the immune system remains a high priority. In the SIV/rhesus macaque model of AIDS, we have shown that loss of CD4+ central memory T cells plays a crucial role in immunodeficiency development, and the results from the proposed studies will elucidate the mechanisms responsible for this loss. This knowledge will provide the opportunity to develop novel therapies aimed at preventing immune damage in HIV+ subjects, even in individuals with uncontrolled viral replication.